Autophagy

Autophagy, also called autophagocytosis, the degradation of worn, abnormal, or malfunctioning cellular components that takes place within organelles known as lysosomes. Autophagy serves housekeeping functions, enabling the breakdown and recycling of cellular materials, and helps balance energy demands during periods of stress. The term autophagy was introduced in 1963 by Belgian cytologist and biochemist Christian René de Duve, whose work also provided the first evidence for the involvement of lysosomes in the autophagic process.

Three types of autophagy are known: macroautophagy, microautophagy, and chaperone-mediated autophagy. Cells rely primarily on macroautophagy, in which worn or damaged cellular materials in cytosolic regions (the fluid-filled areas surrounding organelles) of cells are engulfed by an autophagosome (vesicles with double membranes that deliver their contents to lysosomes, where the materials are degraded). In microautophagy, cellular components are engulfed directly via invaginations of the lysosomal membrane. Chaperone-mediated autophagy is a selective process, whereby a protein known as hsc70 chaperone recognizes and binds to protein substrates containing a certain amino acid motif. The targeted substrate is carried to the lysosome, where it then translocates across the membrane via a receptor-mediated process.

Multiple genes encode the various components of the autophagy machinery required for sequestration, transport, degradation, and recycling of cellular materials. Enzymes encoded by several autophagy genes conjugate (join together), thereby enhancing enzyme activity, particularly during the formation of the autophagosome. A number of nonspecific cellular pathways are also critical to autophagy, including various secretory and endocytic (engulfment) pathways. In addition, the cytoskeleton appears to serve multiple functions in autophagy, key among them the role of microtubules in facilitating autophagosome transport in mammalian cells.

In addition to its housekeeping and stress-response functions, autophagy also contributes to immunity, helping to defend cells against disease-causing organisms and participating in antigen presentation. Autophagy also is involved in programmed cell death, helping eliminate apoptotic cells during embryonic development and aiding death processes in apoptosis-defective cells. Autophagy can also protect against cell death by providing nutrients to cells during periods of starvation. In cancer, autophagy appears to both prevent and, under certain conditions, promote tumour progression. The abnormal accumulation of autophagic vesicles is associated with multiple neurodegenerative conditions, including Parkinson disease and amyotrophic lateral sclerosis, as well as with myopathy (a disease of skeletal muscle tissue).

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